The present invention relates generally to a method for detecting and measuring lung vascular injury, and, more particularly, to a method for assessing capillary permeability to determine vascular lung injury without requiring the injection of radioactive material or requiring the sampling of blood.
Acute Respiratory Distress Syndrome (ARDS) is a major problem in patients in intensive care units (ICU). While the syndrome appears to have many causes, most etiologies lead to capillary injury and increased permeability pulmonary edema. Interest in this problem has stimulated efforts to quantitatively evaluate capillary injury in the lungs and monitor the time course of this injury and the pulmonary edema which results from it. For example, it has been shown in a series of studies in ARDS patients that one variable which differentiates recovery from acute lung injury from continued deterioration of lung function is the magnitude of capillary permeability-surface area (PS) for tracer exchange as determined by radioisotope indicator dilution studies of the lungs. A less invasive method of monitoring capillary injury would be valuable in close management of fluid and oxygen therapies currently used for these patients. In addition, such a system would be an indicator and a monitor of the effectiveness of new therapies which are under development and are aimed at immunological protection and gene therapy of the lung endothelium.
Generally, three methods are used for measuring major lung vascular functions, principally defined as pulmonary blood flow, exchange surface area of extravascular and intravascular volumes in the lung, and lung vascular permeability. These methods are the gamma emitter scanning (GES) technique using labeled macromolecules and blood markers, positron emission tomography (PET), and indicator dilution (ID). While quite useful, GES and PET are equipment intensive, expensive and require injection of radioactive materials.
In contrast, the indicator dilution method provides very high time resolution with collection times on the order of 30 seconds for the measurement of exchange, flow and volumes in the lung. The conventional radioisotope method requires small radiation doses. Both gamma and beta labels may be used and thus a variety of materials are potential probes of endothelial function. The method has been shown to quantitatively measure extravascular lung water, microvascular PS, and parameters which characterize saturable uptake by the endothelium. Tracers exist which can correct for alterations in capillary surface area in the lung. Parameters derived from such indicator curves are altered by lung vascular damage in animal experiments. Studies can be performed in patients under intensive care and provide measures of microvascular function which alter with severity of respiratory distress. Some tracers can be used as nonradioactive markers, and when appropriate instrumentation is used, can provide rapid readings of pulmonary blood flow and extravascular water volume. Advances in optical methods have allowed the extension of this nonradioactive approach to the measurement of lung vascular PS. There are disadvantages, however. There is no spatial resolution and the computations depend on models of flow distribution. Tracers must be injected. Arterial blood must be sampled for lung applications. The kinetics of transport for larger molecules cannot be measured.
Another method related to indicator dilution is the osmotic transient method. Using radioisotopes, this technique has been applied to the lung in baseline conditions and to the heart. Conventionally, the method relied on maintenance of an isogravimetric lung, injections of radioisotopes, and constant infusions of fairly large amounts of hypertonic solutions. The method produced parameters related to the product of the reflection coefficient for movement of fluid across the capillary barrier and the filtration coefficient (.sigma.K). There was good evidence that the filtration measurement included both the interendothelial and transendothelial movement of interstitial fluid. It has further been shown that hypertonic fluid movement through the lung is a highly sensitive instrument for the measurement of fluid density and could be used to measure the interstitial volume supplying fluid for exchange and the .sigma.K product for endothelium. This method shows that highly sensitive instruments could allow smaller amounts of hypertonic fluid to be infused. The disadvantages of the method are that it relies on step infusions of saline and required withdrawal sampling of lung perfusate for density analysis.
While several methods for minimally invasive assessment of capillary permeability are promising, most require the injection of foreign trace materials and many require blood sampling. Further, although much work has been done investigating the osmotic transients in the lung and other organs, and a body of research on the acoustic and electrical impedance properties of biological tissue exists, no work synthesizing these bodies of knowledge exists and this technique has never been applied to an injured lung. Furthermore, no evidence of the ability of the method to identify changes in capillary transport after acute lung injury has been presented.
What is needed, then, is a method for assessing capillary permeability to determine vascular lung injury without requiring the injection of radioactive material and without requiring the sampling of blood.